Question: In patients with type 2 diabetes mellitus and nephropathy, what is the renoprotective effect of the angiotensin-II–receptor antagonist (ARA) losartan?
Design: Randomized (allocation concealed*), blinded (clinicians, patients, outcome assessors, and statisticians),* placebo-controlled trial with mean follow-up of 3.4 years (the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] Study).
Setting: 250 centers worldwide.
Patients: 1513 patients between 31 and 70 years of age (mean age 60 y, 63% men) who had type 2 diabetes and nephropathy defined as a urinary albumin-to-creatinine ratio ≥ 300 mg/g and a serum creatinine level between 115 and 265 µmol/L (≥ 133 µmol/L for men weighing > 60 kg). Exclusion criteria included type 1 diabetes and nondiabetic renal disease. Follow-up was 99.8%.
Intervention: After stratification by baseline level of proteinuria, patients were allocated to receive losartan, 50 to 100 mg/d (n = 751), or placebo (n = 762). Conventional antihypertensive therapy (excluding angiotensin-I–converting enzyme inhibitors and ARAs) was adjusted to target a systolic and diastolic blood pressure < 140 and < 90 mm Hg, respectively.
Main outcome measures: The primary outcome was the composite of a doubling of the baseline serum creatinine level, end-stage renal disease (ESRD), or death. The secondary outcome was the composite of cardiovascular morbidity or mortality.
Main results: Analysis was by intention to treat. Losartan reduced the risk for the primary composite outcome (unadjusted P = 0.02; P = 0.03 after adjustment for blood pressure), doubling of the baseline serum creatinine level (unadjusted P = 0.006), and ESRD (unadjusted P = 0.002) more than did placebo (Table). However, losartan and placebo did not differ for incidence of death (unadjusted P = 0.88) (Table) or the secondary composite outcome of cardiovascular morbidity or mortality (P = 0.26).
Conclusions: Losartan was renoprotective in patients with type 2 diabetes mellitus and nephropathy. This effect was beyond that attributable to blood pressure control.
Losartan vs placebo for type 2 diabetes and nephropathy at mean 3.4 years†
|Outcomes||Losartan||Placebo||RRR (95% CI)‡|
|Composite outcome§||44%||47%||16% (2 to 28)|
|Doubling of serum creatinine level||22%||26%||25% (8 to 39)|
|End-stage renal disease||20%||26%||28% (11 to 42)|